The primary aim of this proposal is to differentiate the function of Alpha1 and Alpha2 adrenoceptors in the eye and in particular to elucidate the action of presynaptic adrenoceptors including the Alpha 2 presynaptic adrenoceptor in inhibiting release of the adrenergic neural transmitter norepinephrine. The health significance of the study lies in recent evidence that activation of presynaptic adrenoceptors represent a mechanism having wide application in the control of autonomic neurotransmission and tissue response. In the eye, it has been found that both Alpha1 and Alpha2 adrenoceptor agonists decrease intraocular pressure in normal and glaucomatous eyes but by different mechanisms. The studies will involve the measurement of the pupillary, intraocular pressure responses in anesthetized animals to graded electrical stimuation of the preganglionic cervical sympathetic nerve. Then, Alpha1 and Alpha2 adrenoceptor agonists and antagonists will be used to define the extent of the presynaptic inhibition of neurotransmission and the extent to which pre and post synaptic adrenoceptor sites are involved. In addition, recent evidence that opiate receptors (including morphine) and Beta adrenoceptor blocking drugs (including Timolol) may act at the presynaptic adrenergic sites will be investigated. The second aspect of this study deals with the elucidation of the ocular responses to Alpha1 and Alpha2 adrenoceptor agonists and differentiation of their pharmacologic properties. In particular, the studies will establish whether the Alpha2 adrenoceptor agonists clonidine and Alpha methyl catecholamines which are highly active in decreasing intraocular pressure act on the different sites of the Alpha2 receptors (as has been found in other tissues). The Alpha methyl catecholamines are of particular ophthalmic interest for recent observations have established that these drugs may decrease intraocular pressure by the Alpha2 mechanism without pupil dilation (an Alpha1 adrenoceptor mechanism) whereas at higher concentrations Alpha1 and Alpha2 adrenoceptor mediated responses take place.